You are here : Home > Research entities > DMTS > Molecular engineering for Heal ... > Chemical biology laboratory

LBC

Chemical biology laboratory

Our laboratory primarily aims to develop innovative molecular tools to investigate proteins involved in a wide range of pathophysiological processes. In particular, we seek to identify new diagnostic and therapeutic strategies in the context of infectious diseases, chronic disorders, autoimmune diseases, and neurodegenerative conditions.

Published on 26 March 2026
 
​​

LAB LEADER

Laurent Devel
+33 1 69 08 84 67
laurent.devel@cea.fr

​Toxins, transport and therapeutic innovation (Julien Barbier)
 Chemical modifications of proteins (Laurent Devel)

   

Staff

Julien Barbier, CEA Researcher, Team leader ; Laurent Devel, CEA Researcher, Lab leader ; Blaise Gatin-Fraudet, CEA Researcher ; Daniel Gillet, CEA Researcher ; Mireille Moutiez, CEA Researcher ; Robert Thai, CEA Researcher ; Fabrice Beau, CEA Engineer ; Sylvain Pichard, CEA Engineer ; Melissa De Souza, CEA technician ; Carole Malgorn, CEA technician ; Ombeline Pessey, CEA technician ; Zakariya Ait Athmane, PhD student ; Lomane Berthy, PhD student ; Eva Hourou, PhD student ; Georgina Ilieska, PhD student ; Marie Launay, PhD student ; Killian Lucas, PhD student


Collaborations

 

Funding


​Image13.jpg Toxins, transport and therapeutic innovation

We develop broad-spectrum inhibitors that target bacterial toxins by disrupting the host cell's intracellular trafficking machinery. By modulating these pathways, our compounds also exhibit antiviral, anti-intracellular bacterial and anti-parasitic activities. Our work also includes the design of a fragment of the diphtheria toxin as an inhibitor of HB-EGF for the treatment of crescentic glomerulonephritis, a rare kidney disease.

​

Team Leader

Julien BARBIER                                                                                                                                                            Publications

Julien.barbier@cea.fr

 

The Toxins, transport and therapeutic innovation group conducts research in two main domains



DEVELOPMENT OF BROAD-SPECTRUM INHIBITORS OF PATHOGEN AGENTS

We design several families of molecules that inhibit intracellularly-acting plant and bacterial toxins. These compounds function as broad-spectrum inhibitors targeting toxins and diverse pathogens that exploit intracellular trafficking pathways to enter and infect host cells. Consequently, they also exhibit antiviral, anti-intracellular bacterial, and anti-parasitic activities. Since 2010, our work has led to the identification of multiple inhibitors, among them Retro-1, Retro-2, ABMA and C910 (Stechmann et al., 2010; Wu et al., 2017; Wu et al., 2021). The progress made for each of them includes: - the optimization of molecules up to nM EC50s on a chosen target pathogen (Table A) (Noël et al., 2013; Gupta et al., Gupta et al., 2017; Wu et al., 2019; Abdelkafi et al., 2020; Pomel et al., 2022),

- the extension of the range of sensitive toxins and pathogens up to in vivo mouse POC (Table B) (Stechmann et al., 2010; Secher et al., 2015; Harrison et al., 2016; Gupta et al., 2017; Wu et al., 2017; Dai et al., 2017; Dai et al., 2018; Shtanko et al., 2018; Wu et al., 2022; Liu et al., 2022 ; Le Rouzic et al., 2022),

- the move toward deciphering the mechanisms of action (Wu et al., 2017; Wu et al., 2020 ; Wu et al., 2022 ; Wu et al., 2024 ; Obeid et al., 2023) and target identification (Retro-2, Forrester et al., 2020)

-  further preclinical development via with pharmacokinetics and ADME studies. (Vinck et al., 2022)

More recently, new generations of toxin inhibitors have been developed using AI-assisted virtual screening strategies, as well as PROTAC-based approaches. (Michon et al., 2026)

preclinical.jpg

DESIGN OF A POWERFUL INHIBITOR OF HB-EGF FOR THE TREATMENT OF CRESCENTIC GLOMERULONEPHRITIS

Crescentic glomerulonephritis is a rare and severe kidney disease characterized by the rapid destruction of the kidney's filtration units, the glomeruli. It results from an immune aggression against the kidney, involving autoantibodies or immune complexes. This immune injury triggers the expression of a key growth factor, HB-EGF (Heparin-Binding Epidermal Growth Factor), by specialized glomerular cells known as podocytes and parietal epithelial cells. Under the influence of HB-EGF, these cells lose their normal functions, proliferate abnormally, and directly contribute to glomerular destruction.

 

Scientific studies by our collaborator Pierre-Louis Tharaux, INSERM, have demonstrated that blocking HB-EGF can protect glomeruli even in the persistent presence of disease-causing antibodies. However, current treatments rely exclusively on immunosuppression. While they reduce inflammation, they do not target this central mechanism of kidney injury, which explains why a significant proportion of patients still progress to end-stage kidney disease or death.

 

Because membrane-bound HB-EGF is the natural receptor of diphtheria toxin, we leveraged this biological property to engineer a potent and selective HB-EGF inhibitor called DTR8, derived from a non-toxic fragment of the toxin. A first proof-of-concept study in a relevant animal model demonstrated that DTR8 preserves glomerular structure and reduces kidney damage. Our goal is now to develop DTR8 as a novel therapeutic to significantly improve outcomes for patients with crescentic glomerulonephritis.

Image16.png

DTR8 (brown) is an engineered receptor-binding domain of the diphtheria toxin carrying 12 mutations that improve its solubility and affinity for HB-EGF, and decreases its immunogenicity and antigenicity.

​ Image21.jpg

Left: podocytes from a pig kidney produce HB-EGF and proliferate as a result when put on a tissue culture plate. Right: in the presence of DTR8, their proliferation is prevented (photo: Pierre-Louis Tharaux, INSERM).

Chemical modifications of proteins

Team Leader

Laurent DEVEL                                                                                                                                                           Publications

laurent.devel@cea.fr

​​equipe.png

Second row, from left to right: Robert Thaï, Killian Lucas, Zakariya Ait Athmane, Carole Malgorn, Lomane Berthy, Paul Berjot, and Blaise Gatin-Fraudet.

First row, from left to right: Mireille Moutiez, Marie Launay, Mélissa De Souza, Alice Saunier, Laurent Devel, Georgina Ilieska, and Fabrice Beau.

Medallion on the left: Irène Barthelet, Medallion on the right: Gabriel Chevallier.


​The “Chemical modifications of proteins" Team develops innovative technologies at the interface of chemical biology, medicinal chemistry, chemoproteomics, molecular imaging, and nanomedicine to study proteins in complex biological systems (Figure 1)​

fig 1.png

Figure 1

Our research focuses on the development of diagnostic and therapeutic tools targeting chronic inflammatory diseases, fibrosis, cardiovascular diseases, autoimmune disorders, and neurodegenerative diseases

 

Key words: Protein Chemistry - ligand-directed chemistry – Chemoproteomics - Activity-based Probes – Metalloproteases - Molecular Imaging – Radiolabeling – Nanomedicine - Biomarkers - Antibody-drug Conjugates - Targeted Drug Delivery - Translational Medicine – Target validation.​

Metalloprotease Inhibitors and Therapeutic Target Validation

​Our laboratory designs selective enzyme inhibitors, particularly inhibitors targeting matrix metalloproteases (MMPs) involved in numerous human diseases.

Our research aims to:

  • Identify novel therapeutic targets
  • Understand the role of proteases in cardiovascular diseases and cancer
  • Develop new drug candidates for inflammatory and respiratory diseases
  • Support translational drug discovery programs

    Our laboratory designs selective enzyme inhibitors, particularly inhibitors targeting matrix metalloproteases (MMPs) involved in numerous human diseases.

    Our research aims to:

    • Identify novel therapeutic targets
    • Understand the role of proteases in cardiovascular diseases and cancer
    • Develop new drug candidates for inflammatory and respiratory diseases
    • Support translational drug discovery programs

Activity-Based Probes and Chemoproteomics

We develop ligand-directed chemistry enabling selective labelling of proteins or active enzymes in their physiological environment (Figure 2).

These technologies allow:​​​

  • Functional profiling of active proteases in living tissues
  • Sensitive detection and quantification of proteins in biological fluids
  • Discovery of diagnostic and prognostic biomarkers
  • Investigation of receptor trafficking and signalling pathways

Our chemoproteomics strategies contribute to the development of targeted therapies and precision medicine.

labe.png​

Figure 2

​

Molecular Imaging and In Vivo Drug Fate Studies

​

Our team develops molecular imaging agents and radiolabelling strategies to investigate the in vivo fate of therapeutic compounds (Figure 3).

Our research includes:

  • Imaging of disease-associated enzymes
  • Pharmacokinetic and biodistribution studies
  • Dual tracking of complex biotherapies such as antibody-drug conjugates (ADCs)

    These studies support drug optimization and clinical translation.​
Image20.png

​

Figure 3


Nanomedicine and Smart Biosensors

Our laboratory develops innovative nanomedicine strategies for targeted drug delivery and non-invasive diagnostics.

We design:

  • Lipid-based nanoparticles for imaging and treatment of atherosclerotic plaques
  • Therapeutic nanocarriers for targeted drug delivery
  • Enzyme-responsive nanosensors for early disease detection, including liver fibrosis​
    ​

​

selected publications

Michon M, Curpanen S, Pessey O, Thai R, Gaillard JC, Herbette G, Hinsinger K, Gillet D, Armengaud J, Cintrat JC, Barbier J. (2026).

     Synthesis and biological evaluation of Retro-2-based PROTACs reveal PEG-linker length and warhead impact on GSPT1 degradation. Eur J Med Chem. 307, 118645. doi.10.1016/j.ejmech.2026.118645

Wu Y, Huang J, Zhang F, Guivel-Benhassine F, Hubert M, Schwartz O, Xiao W, Cintrat JC, Qu L, Barbier J, Gillet D, Cang C. (2024)

Endolysosomal channel TMEM175 mediates antitoxin activity of DABMA. FEBS J. 291, 4142-4154. doi: 10.1111/febs.17242

Wu Y, Taisne C, Mahtal N, Forrester A, Lussignol M, Cintrat JC, Esclatine A, Gillet D, Barbier J. (2023)

Autophagic Degradation Is Involved in Cell Protection against Ricin Toxin. Toxins (Basel), 15, 304. doi: 10.3390/toxins15050304.

Obeid S, Berbel-Manaia E, Nicolas V, Dennemont I, Barbier J, Cintrat JC, Gillet D, Loiseau PM, Pomel S. (2023)

Deciphering the mechanism of action of VP343, an antileishmanial drug candidate, in Leishmania infantum. iScience. 26, 108144. doi: 10.1016/j.isci.2023.108144.

Le Rouzic A, Fix J, Vinck R, Kappler-Gratias S, Volmer R, Gallardo F, Eléouët JF, Keck M, Cintrat JC, Barbier J, Gillet D, Galloux M. (2023)

A New Derivative of Retro-2 Displays Antiviral Activity against Respiratory Syncytial Virus. Int J Mol Sci. 25, 415. doi: 10.3390/ijms25010415.

Wu Y, Mahtal N, Paillares E, Swistak L, Sagadiev S, Acharya M, Demeret C, Werf SV, Guivel-Benhassine F, Schwartz O, Petracchini S, Mettouchi A, Caramelle L, Couvineau P, Thai R, Barbe P, Keck M, Brodin P, Machelart A, Sencio V, Trottein F, Sachse M, Chicanne G, Payrastre B, Ville F, Kreis V, Popoff MR, Johannes L, Cintrat JC, Barbier J, Gillet D, Lemichez E. (2022)

C910 chemical compound inhibits the traffiking of several bacterial AB toxins with cross-protection against influenza virus. iScience. 25, 104537. doi: 10.1016/j.isci.2022.104537.

Vinck R, Nguyen LA, Munier M, Caramelle L, Karpman D, Barbier J, Pruvost A, Cintrat JC, Gillet D. (2022)

In Vivo Sustained Release of the Retrograde Transport Inhibitor Retro-2.1 Formulated in a Thermosensitive Hydrogel. Int J Mol Sci. 23, 14611. doi: 10.3390/ijms232314611.

Liu H, Jiang C, Wu Y, Wu M, Wu J, Zhao G, Sun J, Huang X, Li J, Sheng R, Barbier J, Cintrat JC, Gillet D, Su W. (2022)

Antiviral Effects of ABMA and DABMA against Influenza Virus In Vitro and In Vivo via Regulating the Endolysosomal Pathway and Autophagy. Int J Mol Sci. 23, 3940. doi: 10.3390/ijms23073940.

Pomel S, Cojean S, Pons V, Cintrat JC, Nguyen L, Vacus J, Pruvost A, Barbier J, Gillet D, Loiseau PM. (2021)

An adamantamine derivative as a drug candidate for the treatment of visceral leishmaniasis. J Antimicrob Chemother. 76, 2640-2650. doi: 10.1093/jac/dkab226.

Kali, S., Jallet, C., Azebi, S., Cokelaer, T., Da Fonseca, J. P., Wu, Y., Barbier, J., Cintrat, J.-C., Gillet, D., & Tordo, N. (2021). Broad spectrum compounds targeting early stages of rabies virus (RABV) infection. Antiviral Research, 188, 105016. doi.org/10.1016/j.antiviral.2021.105016

Pomel, S., Cojean, S., Pons, V., Cintrat, J.-C., Nguyen, L., Vacus, J., Pruvost, A., Barbier, J., Gillet, D., & Loiseau, P. M. (2021).

An adamantamine derivative as a drug candidate for the treatment of visceral  leishmaniasis. The Journal of Antimicrobial Chemotherapy. doi.org/10.1093/jac/dkab226

Johansson, K., Willysson, A., Kristoffersson, A.-C., Tontanahal, A., Gillet, D., Ståhl, A.-L., & Karpman, D. (2020). Shiga Toxin-Bearing Microvesicles Exert a Cytotoxic Effect on Recipient Cells Only When the Cells Express the Toxin Receptor. Frontiers in Cellular and Infection Microbiology, 10, 212. doi.org/10.3389/fcimb.2020.00212

Abdelkafi, H., Michau, A., Pons, V., Ngadjeua, F., Clerget, A., Ait Ouarab, L., Buisson, D.-A., Montoir, D., Caramelle, L., Gillet, D., Barbier, J., & Cintrat, J.-C. (2020). Structure-Activity Relationship Studies of Retro-1 Analogues against Shiga Toxin. Journal of Medicinal Chemistry, 63, 8114–8133. doi.org/10.1021/acs.jmedchem.0c00298

Willysson, A., Ståhl, A.-L., Gillet, D., Barbier, J., Cintrat, J.-C., Chambon, V., Billet, A., Johannes, L., & Karpman, D. (2020). Shiga Toxin Uptake and Sequestration in Extracellular Vesicles Is Mediated by Its  B-Subunit. Toxins, 12, 449 . doi.org/10.3390/toxins12070449

Forrester, A., Rathjen, S. J., Daniela Garcia-Castillo, M., Bachert, C., Couhert, A., Tepshi, L., Pichard, S., Martinez, J., Munier, M., Sierocki, R., Renard, H. F., Augusto Valades-Cruz, C., Dingli, F., Loew, D., Lamaze, C., Cintrat, J. C., Linstedt, A. D., Gillet, D., Barbier, J., & Johannes, L. (2020). Functional dissection of the retrograde Shiga toxin trafficking inhibitor Retro-2. Nature Chemical Biology, 16, 327–336. doi.org/10.1038/s41589-020-0474-4

Mahtal, N., Wu, Y., Cintrat, J. C., Barbier, J., Lemichez, E., & Gillet, D. (2020). Revisiting old ionophore lasalocid as a novel inhibitor of multiple toxins. Toxins, 12, 1–13. doi.org/10.3390/toxins12010026

Wu, Y., Boulogne, C., Carle, S., Podinovskaia, M., Barth, H., Spang, A., Cintrat, J. C., Gillet, D., & Barbier, J. (2020). Regulation of endo-lysosomal pathway and autophagic flux by broad-spectrum antipathogen inhibitor ABMA. FEBS Journal, 287, 3184-3199. doi.org/10.1111/febs.15201

Wu, Y., Pons, V., Noël, R., Kali, S., Shtanko, O., Davey, R. A., Popoff, M. R., Tordo, N., Gillet, D., Cintrat, J. C., & Barbier, J. (2019). DABMA: A Derivative of ABMA with improved broad-spectrum inhibitory activity of toxins and viruses. ACS Medicinal Chemistry Letters, 10, 1140–1147. doi.org/10.1021/acsmedchemlett.9b00155

Mahtal, N., Brewee, C., Pichard, S., Visvikis, O., Cintrat, J. C., Barbier, J., Lemichez, E., & Gillet, D. (2018). Screening of a Drug Library Identifies Inhibitors of Cell Intoxication by CNF1. ChemMedChem, 13, 754–761. doi.org/10.1002/cmdc.201700631

Barbier, J., & Gillet, D. (2018). Ribosome inactivating proteins: From plant defense to treatments against human misuse or diseases. Toxins, 10, 10–13. doi.org/10.3390/toxins10040160​


​